Compound for treating or preventing hyperuricemia or gout

ABSTRACT

The invention discloses a class of compounds for treating or preventing hyperuricemia or gout, which is a compound shown in general formula (I) or a pharmaceutically acceptable salt. These compounds and their pharmaceutically acceptable salts in the invention are useful for the promotion of uric acid excretion to treat or prevent hyperuricemia or gout.

TECHNICAL FIELD

This invention belongs to the field of medicinal chemistry andparticularly relates to a class of(4-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone derivatives,their compositions, and their applications in medicine.

BACKGROUND OF THE INVENTION

Gout is a metabolic disease caused by chronically elevated serum uricacid (sUA) levels (hyperuricemia) due to the disorder of purinemetabolism and/or from insufficient renal elimination of uric acid.Deposition of the needle-like crystals of urate in the joints leads topainful inflammatory arthritis. Hyperuricemia, defined as sUAconcentration higher or equal to 6.8 mg/dL, may result in theprecipitation of urate as mono-sodium salt in the synovial fluid of thehuman soft tissue, the cartilage of the peripheral joint, the auricle ofthe ear, and the olecranon bursa of the elbow. When such symptoms arepresents, it can be diagnosed as gout. (Terkeltaub R A. CrystalDeposition Diseases. In: Goldman L, Aus-iello D, eds. The Cecil Textbookof Medicine, 23rd ed. Philadelphia, Pa.: Saunders Elsevier Co;2008:2069-2075; Richette P, Bardin T. Gout. Lancet. 2010,375(9711):318-328)

Gout is the common type of inflammatory arthritis and has an incidenceof approximately 1%-2%. The incidence in the developed countries isrelatively high, as a survey of 2007-2008 reported there were about 8.3million of gout patients in the US. In China, the incidence of gout hasdramatically increased in the past decade. It is reported that thenumber of gout patients in China has exceeded 50 million, and theproportion of men with gout is much higher than that of women.

In the present, gout medications involve short-term treatment for painrelief and reduction of inflammation during an acute attack, theinhibition of uric acid production, and the promotion of uric acidexcretion. Medicine for the treatment of acute attack of gout mainlyinclude colchicine, non-steroidal anti-inflammatory drugs (NSAIDs),adrenocorticotropic hormone, and glucocorticoid.

Long-term medications of gout involve decreasing the formation of uricacid and/or increasing uric acid renal excretion. Allopurinol and uloricare the more often used drugs on decreasing the formation of uric acid.The mechanism of these drugs is to reduce the formation of uric acid byinhibiting the xanthine oxidase needed for the transformation of purineto uric acid. Uricosurics are the second class of urate lowering therapycurrently available, which act by increasing uric acid renalelimination. They mainly include probenecid, sulphinpyrazone, andbenzbromarone etc.

The treatment of acute gout attacks can only control the symptoms andrelieve the pain of the patients, but it cannot reduce the concentrationof sUA. Colchicine is very toxic, often accompanied by common adversereactions such as diarrhea, vomiting and abdominal pain spasms.Allopurinol is one of the xanthine oxidase inhibitors. It needs to beused in high dose, and for some people can cause fatal Stevens Johnsonsyndrome (skin erythema multiforme), often accompanied by stomachdiscomfort, nausea, diarrhea, headache, fever, loss of appetite, weightloss, pain in urination, hematuria and other side effects. Anotherxanthine oxidase inhibitor is called uloric (febuxostat), which waslaunched in Europe and the US in 2009. Although uloric shows goodefficacy in lowering uric acid levels in the body, it also has veryserious side effects such as cardiovascular problem and gastrointestinaldiscomfort, potentially causing headaches and liver injury.Benzbromarone has a good uricosuric efficacy, but it leads to fatalliver injury. Both probenecid and sulfinpyrazone are uricosuric agentswith high dose administration in poor efficacy and bad side effects.

The mechanism of uricosurics involves the inhibition of there-absorption of uric acid in the proximal tubular cells to increase therenal excretion of uric acid and reduce the concentration of blood uricacid. About 70% of uric acid excretion in human is by the kidneys, andabout 80-85% of hyperuricemia patients is caused by uric acid excretiondisorder. (Cheeseman C. Solute carrier family 2, member 9 and uric acidhomeostasis. Current Opinion in Nephrology and Hypertension, 2009, 18(5): 428-432)

Uric acid excretion plays a very important role in the treatment ofhyperuricemia and gout. Human urate anion transporter 1 (hURAT1) islocated in the proximal tubular epithelial cell membrane, and it belongsa super family member of an organic anion transporter (OAT), which isencoded by SLC22A12 gene. Its cDNA has several mutations that cause uricacid metabolism abnormally. A Meta analysis showed that this gene has0.13% variables contributed to serum uric acid level. (So A, Thorens B.Uric acid transport and disease. Journal of Clinical Investigation.,2010, 120 (6): 1791-1799)

The URAT1 controls more than 90% of the uric acid re-absorption afterglomerular filtration. Therefore, selective inhibition of URAT1 candecrease the re-absorption of uric acid and promote the excretion ofuric acid in the kidneys to reduce uric acid levels in the body.(Michael F W, Jutabha P, Quada B. Developing potent human uric acidtransporter 1 (hURAT1) inhibitors. Journal of Medicinal Chemistry. 2011,54:2701-2713)

Currently, benzbromarone as the URAT1 inhibitor is still widely used inthe market for the treatment of gout. Its chemical name is(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-benzofuran-3-yl)methanone, whichwas developed by France Snaofi-Synthelabo company and launched in 1976.It is the most effective uricosuric agent in the market and has beenused for nearly 40 years. But the use of benzbromarone has not beenapproved in the US and was withdrawn from most European markets in 2003due to its side effect of severe liver toxicity. (Jansen T L, Reinders MK, van Roon E N, et al. Benzbromarone withdrawn from the Europeanmarket: another case of “absence of evidence is evidence of absence”.Clinical Experimental Rheumatology, 2004, 22(5): 651) Anotherdisadvantage is that it has a strong inhibitory effect on the liverCYP2C9 enzyme. However, more than 20 countries, such as China, Germany,Japan, Brazil, and New Zealand still widely use it because of the lackof good gout drugs on the market.

Studies have shown that the fulminant or fatal liver injury ofbenzbromarone has been associated with its reactive metabolites. Apossible mechanism of liver toxicity may involve the bioactivation ofbenzbromarone through sequential hydroxylation of the benzofuran ring toform 6-hydroxy-benzbromarone and a catechol by CYP2C9, which can befurther oxidized by P450s enzymes to a reactive quinone metabolitecapable of adducting thiol reagents/cysteine residues. (Matthew G.McDonald, Rettie A E. Sequential metabolism and bioactivation of thehepatotoxin benzbromarone: formation of glutathione adducts from acatechol intermediate. Chemical Research in Toxicology. 2007, 20(12):1833-1842)

Benzbromarone also has other side effects, such as diarrhea, stomachdiscomfort, nausea, digestive system symptoms, skin allergies such asmacula, flush, itching, and so on.

Currently, severe side effects from either the uricosuric agents orxanthine oxidase inhibitors have greatly affected the long-term use ofthese gout medicines. Therefore, it is critical to develop gout drugsthat are highly effective and have low toxicity.

BRIEF SUMMARY OF THE INVENTION

A class of novel (4-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanonederivatives as URAT1 inhibitors, methods for their preparation, andrelated synthetic intermediates and compositions are provided. The testresults both in vitro and in vivo showed that compounds provided by thisinvention can significantly improve the inhibitory effect on URAT1, aswell as significantly increase uric acid excretion in mice and reducethe toxicity to normal liver cells in comparison with benzbromarone. Theoral maximum tolerated dose of acute toxicity test in rats showed thatthe toxicity of the compound provided by the invention was much lowerthan that of benzbromarone. The studies have shown that the compoundprovided by the invention is highly effective in uric acid excretion andhas low toxicity.

Another purpose of the present invention is to provide a pharmaceuticalcomposition containing(4-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone derivatives.

Additionally, the compounds of(4-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl) methanone described hereinare useful in the prevention or treatment of hyperuricemia, nephropathyor gout.

Embodiments of the invention can be achieved by the following measures:

The compounds of the present invention are represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, deuterium, halogen, cyano, hydroxyl, C₁₋₅ alkyl, substitutedC₁₋₅ alkyl, C₁₋₃ alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃ alkylthio, orsubstituted C₁₋₃ alkylthio in one or more;

R³ is selected from the substituted or unsubstituted group consisting ofC₁₋₄ alkyl or C₃₋₄ cycloalkyl, and the substituents are independentlyselected from the group consisting of deuterium, halogen, C₁₋₂ alkyl orC₃₋₄ cycloalkyl.

R⁴ and R⁵ are independently selected from the group consisting ofhalogen, deuterium, cyano, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkyl,substituted C₁₋₃ alkyl, C₁₋₃ alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃alkylthio, or substituted C₁₋₃ alkylthio; wherein the substituents inR¹, R², R⁴, and R⁵ are independently selected from deuterium, halogen,C₁₋₃ alkyl, C₃₋₄ cycloalkyl or C₁₋₃ alkoxy.

R¹, R², R⁴ and R⁵ in the invention can be selected from one, two or morethan two of the defined groups individually. When R¹, R², R⁴ or R⁵ areselected for two or more than two, these groups are located at thecorresponding sites of phenyl ring or imidazo[1,2-a]pyridyl ring. Forexample, when R⁴ uses two groups, the two groups can be at 2 and 3positions in the 4-hydroxy phenyl, respectively.

In one embodiment, each R¹ or R² is independently selected fromhydrogen, deuterium, halogen, cyano, hydroxyl, C₁₋₅ alkyl, substitutedC₁₋₅ alkyl, C₁₋₃ alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃ alkylthio, orsubstituted C₁₋₃ alkylthio; the substituents are selected fromdeuterium, halogen, C₁₋₃ alkyl, C₃₋₄ cycloalkyl or C₁₋₃ alkoxy.

In another preferred embodiment, R¹ and R² are independently selectedfrom one or more of hydrogen, deuterium, fluorine, chlorine, bromine,cyano, hydroxyl, C₁₋₃ alkyl, substituted C₁₋₃ alkyl, C₁₋₃ alkoxy, orsubstituted C₁₋₃ alkoxy; the substituents are selected from deuterium,halogen, C₁₋₃ alkyl, C₃₋₄ cycloalkyl or C₁₋₃ alkoxy.

In some embodiments, R¹ or R² are independently selected from one ormore of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C₁₋₃alkyl, halogenated C₁₋₃ alkyl or C₁₋₃ alkoxy.

In some embodiments, R¹ and R² are independently selected from hydrogen,deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, methoxy,ethoxy, trifluoromethyl and so on.

In some embodiments, R³ is independently selected from C₁₋₃ alkyl,substituted C₁₋₃ alkyl, C₃₋₄ cycloalkyl or substituted C₃₋₄ cycloalkyl;The substituents are selected from deuterium, halogen, C₁₋₂ alkyl orC₃₋₄ cycloalkyl.

In some embodiments, R³ is selected from C₂₋₃ alkyl or C₃₋₄ alkyl alkyl.

In some embodiments, R³ is selected from ethyl or cyclopropyl.

In some embodiments, R⁴ and R⁵ are independently selected from hydrogen,deuterium, halogen, cyano, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkyl,substituted C₁₋₃ alkyl, C₁₋₃ alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃alkylthio or substituted C₁₋₃ alkylthio; the substituents are selectedfrom deuterium, halogen, C₁₋₃ alkyl, C₃₋₄ cycloalkyl or C₁₋₃ alkoxy.

In some embodiments, R⁴ and R⁵ are independently selected from one ormore of hydrogen, deuterium, halogen, cyano, ethylene, acetylene, C₁₋₂alkyl, substituted C₁₋₂ alkyl, C₁₋₂ alkoxy, substituted C₁₋₂ alkoxy,C₁₋₂ alkylthio or substituted C₁₋₂ alkylthio; the substituents areselected from deuterium, halogen, C₁₋₂ alkyl, C₃₋₄ cycloalkyl or C₁₋₃alkoxy.

In some embodiments, R⁴ and R⁵ are independently selected from one ormore of hydrogen, deuterium, halogen, cyano, C₁₋₂ alkyl, halogenatedC₁₋₂ alkyl, C₁₋₂ alkoxy or C₁₋₂ alkylthio.

In some embodiments, R⁴ and R⁵ are independently selected from one ormore of hydrogen, deuterium, halogen, cyano, methyl, ethyl, methoxy,ethoxy, trifluoromethyl, methylthio or ethylthio.

In some embodiments, R⁴ is selected from one or more of halogens, and R⁵is selected from cyano.

In some embodiments, “pharmaceutically acceptable salts” are saltsformed by the compounds in the invention with acids, which are obtainedby reacting free bases of the parent compounds with inorganic acids ororganic acids, wherein the inorganic acids and the organic acids include(but not limited to): for example, hydrochloric acid, hydrobromic acid,nitric acid, phosphoric acid, acetic acid, propanoic acid, acrylic acid,oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid,hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid,phthalic acid, methanesulfonic acid, ethanesulfonic acid,1-naphthalenesulphonic acid, 2-naphthalenesulphonic acid,p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid andthe like.

A compound of the present invention or its pharmaceutically acceptablesalt, in which the compound is selected from:

-   (3,5-Dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;-   (2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone;-   (3-Chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;-   (3-Chloro-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;    3-Chloro-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile;-   (3-Bromo-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;-   (2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-iodo-5-methylphenyl)methanone;    (2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-iodophenyl)methanone;    5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile;    (3-Chloro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanone;    (3-Bromo-5-chloro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone;    (3-Chloro-4-hydroxy-5-iodophenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone;    5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-methylbenzonitrile;    (2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone;    (3-Bromo-4-hydroxy-5-(trifluoromethyl)phenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;    (3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-methylimidazo[1,2-a]pyridine-3-yl)methanone;    (3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-methoxyimidazo[1,2-a]pyridine-3-yl)methanone;    3-Bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile;    5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile;    5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-3-fluoro-2-hydroxybenzonitrile;    (3,5-Dibromo-4-hydroxyphenyl)(2-propylimidazo[1,2-a]pyridine-3-yl)methanone;    (2-Ethylimidazo[1,2-a]pyridine-3-yl)(2-ethylsulfanyl-4-hydroxyphenyl)methanone;    (3-Bromo-5-chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;    (3-Bromo-5-fluoro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanone;    (2-Ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)(3-fluoro-4-hydroxy-5-iodophenyl)methanone;    (3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxyimidazo[1,2-a]pyridin-3-yl)methanone;    (6-Bromo-2-ethyl-7-methylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone;    (3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone;    3-(3,5-Dibromo-4-hydroxyphenyl)-2-ethylimidazo[1,2-a]pyridine-6-carbonitrile;    (2-Deuterium-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;    (2-Deuterium-3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;    (6-Deuterium-2-ethylimidazo[1,2-a]pyridine-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone;    (2-Cyclopropylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone;    3-Bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile    hydrogen chloride; and    5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile    hydrogen chloride.

The compounds of the present invention can be prepared by the followingsynthetic methods:

In the general scheme 1, the substituted 2-aminopyridine was reactedwith acyl chloride to give the corresponding amide, which was furtherreacted with substituted 2-bromo-1-phenylethanone to obtain thecorresponding (imidazo[1,2-a]pyridin-3-yl)-(phenyl)methanone. Thecompound may be the final product, or the target product was obtained bydemethylation, halogenation and/or other reactions.

In the general scheme 2, the substituted acetophenone was reacted withthe corresponding ester to give 1,3-diketone compound which was reactedwith the corresponding 2-aminopyridine to obtain(imidazo[1,2-a]pyridin-3-yl)-(phenyl)methanone. The target compound wasafforded by demethylation, halogenation and/or other reactions.

The definition of each group in the synthetic schemes is as describedbelow.

Unless otherwise stated, the following terms used in the claims andinstructions have the meanings given below.

“Hydrogen” refers to protium (1H) which is a main stable isotope ofhydrogen.

“Deuterium” is a stable isotope of hydrogen and also referred to asheavy hydrogen, and its symbol of element is D.

“Halogen” refers to fluorine atom, chlorine atom, bromine atom or iodineatom.

“Alkyl” is a saturated aliphatic group having 1 to 20 carbon atoms,including a straight-chain group and a branched-chain group (thenumerical range (e.g., 1 to 20) mentioned in the present applicationmeans that this group (alkyl in this case) may contain one carbon atom,two carbon atoms, three carbon atoms or even twenty carbon atoms). Analkyl containing 1 to 4 carton atoms is called a low-level alkyl. Alow-level alkyl without any substituent group is called an unsubstitutedlow-level alkyl, for example, methyl, ethyl, propyl, 2-propyl, n-butyl,isobutyl, tert-butyl or the like. The alkyl may be substituted orunsubstituted.

“Alkoxy” represents —O— (unsubstituted alkyl) and —O— (unsubstitutedcycloalkyl), and further represents —O— (unsubstituted alkyl).Representative examples include but are not limited to methoxy, ethoxy,propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy,cyclohexyloxy, or the like.

“Alkylthio” represents the —S— (unsubstituted alkyl) and —S—(unsubstituted cycloalkyl) groups, further indicates the —S—(unsubstituted alkyl). Representative examples include but not limitedto methionyl, ethylthio, propylthio, butylthio, or cyclopropylthio,cyclobutylthio, cyclopentythio, cyclohexylthio, the like.

“Alkenyl” represents a linear or branched hydrocarbyl group having from2 to 7 carbon atoms and, in some embodiments, from 2 to 6 carbon atomsor 2 to 4 carbon atoms. Representative examples include for example,ethenyl, propenyl, allyl, and the like.

“Alkynyl” represents a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical having from 2 to 7 carbon atomsand, in some embodiments, from 2 to 6 carbon atoms or 2 to 4 carbonatoms. Representative examples include ethynyl, propynyl, propargyl, andthe like.

“Cycloalkyl” represents a single or double ring alkyl group with morethan 3 carbon atoms, including but not limited to cyclopropyl,cyclobutyl, cyclohexenyl, and dicycloheptyl groups.

“Cyano” represents the group —CN.

“Pharmaceutically acceptable salts” are salts formed by the compounds offormula (I) with organic acids or inorganic acids, and represent saltsmaintaining the bioavailability and properties of the parent compounds.These salts include:

(1) salts formed by the compounds with acids, which are obtained byreacting free bases of the parent compounds with inorganic acids ororganic acids, wherein the inorganic acids include (but not limited to):for example, hydrochloric acid, hydrobromic acid, nitric acid,phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid,perchloric acid and the like; the organic acids include (but not limitedto): for example, acetic acid, propanoic acid, acrylic acid, oxalicacid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoicacid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid,methanesulfonic acid, ethanesulfonic acid, 1-naphthalenesulphonic acid,2-naphthalenesulphonic acid, p-toluenesulfonic acid, salicylic acid,tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid,malonic acid and the like; and

(2) salts generated by substituting acidic protons in the parentcompounds with metal ions or coordinating the acidic protons in theparent compounds with organic alkalis, wherein the metal ions include,for example, alkali metal ions, alkaline-earth metal ions or aluminumions; and the organic alkalis include, for example, ethanolamine,diethanolamine, triethanolamine, trometamol, N-methylglucamine and thelike.

“Pharmaceutical composition” refers to the mixture of one or morecompounds described herein, or their pharmaceutically acceptable saltsand prodrugs, together with other chemical components, such aspharmaceutically acceptable carriers and excipients. The purpose of thepharmaceutical composition is to promote the drug delivery of thecompound to the organism.

In the following section, unless specifically restricted, compounds (I),which are active ingredients of therapeutic agents, including all theirpharmaceutically acceptable salts, should be understood to fall into thescope of this invention. In this specification, they are simply referredto as compounds of formula (I) for convenience.

The invention comprises a pharmaceutical composition, which comprisesany compound of the invention, its pharmaceutically acceptable salt orits easily hydrolyzed prodrug ester as an active ingredient,supplemented by pharmaceutically acceptable excipients.

The above compounds of formula (I) in the invention have been confirmedin the following embodiments, they can significantly improve theinhibitory effect on URAT1, significantly increase uric acid excretionin mice, and the toxicity is far lower than that of benzbromoron.Therefore, the compound provided by the present invention has moreexcellent uric acid excretion effect and higher safety. Based on theseproperties, a compound or a pharmaceutically acceptable salt thereof canbe used in the preparation of uricosuric drug for the treatment of thediseases related to the disorder of uric acid excretion, especially usedin the treatment or prevention of hyperuricemia, nephrosis or gout.

SPECIFIC IMPLEMENTATION METHODS Example 1: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]-pyridin-3-yl)methanone(4)

Step A: To a mixture of 2-aminopyridine (2.0 g, 21.3 mmol) andtriethylamine (2.58 g, 25.5 mmol) in dichloromethane (20 mL) was addedpropionyl chloride (2.07 g, 22.4 mmol) dropwise in an ice-water bath.After addition, the reaction mixture was warmed to room temperature andstirred overnight, diluted with water (40 mL), extracted withdichloromethane (40 mL×3). The combined organic layer was washed withbrine (30 mL), dried over anhydrous sodium sulfate, concentrated undervacuum. The residue was purified by flash column chromatography onsilica gel (eluted with ethyl acetate/petroleum ether=1:15-1:10) to giveN-(pyridine-2-yl)propionamide (1) (2.74 g) with 85.6% yield.

Step B: A mixture of compound 1 (300 mg, 2.0 mmol) and2-bromo-1-(4-methoxyphenyl)-ethanone (460 mg, 2.0 mmol) in toluene (10mL) was heated under reflux for 48 h. The reaction mixture was cooled toroom temperature, diluted with water (30 mL), adjusted to pH 8-9 withsaturated potassium carbonate, extracted with dichloromethane (40 mL×3).The combined organic layer was dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:30-1:1) to afford(2-ethylimidazo[1,2-a]pyridine-3-yl)(4-methoxyphenyl)methanone (2) (254mg) with 45.3% yield. ¹H NMR (DMSO-d6, 500 MHz) δ 9.18 (d, J=7.0 Hz,1H), 7.74-7.69 (m, 3H), 7.58-7.55 (m, 1H), 7.17-7.14 (m, 1H), 7.09 (d,J=8.5 Hz, 2H), 3.87 (s, 3H), 2.45 (q, J=7.5 Hz, 2H), 1.11 (t, J=7.5 Hz,3H). MS (EI, m/z): 281.1 [M+H]⁺.

Step C: Boron tribromide (0.6 mL, 1.0 M in toluene) was added dropwiseinto a solution of compound 2 (80 mg, 0.285 mmol) in anhydrousdichloromethane (6 mL) in an ice-water bath. After addition, thereaction mixture was warmed to room temperature, stirred overnight,poured into ice-water (30 mL), adjusted to pH 7-8 with saturated sodiumbicarbonate, and extracted with ethyl acetate (40 mL×2). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:20-1:1) to afford(2-ethylimidazo[1,2-a]-pyridine-3-yl)(4-hydroxyphenyl)methanone (3) (67mg) with 88.3% yield. ¹H NMR (DMSO-d6, 300 MHz) δ 10.29 (s, 1H), 9.11(d, J=6.6 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.62-7.51 (m, 3H), 7.15-7.11(m, 1H), 6.90 (d, J=8.4 Hz, 2H), 2.45 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5Hz, 3H). MS (EI, m/z): 267.2 [M+H]⁺.

Step D: To a mixture of compound 3 (67 mg, 0.252 mmol) and sodiumacetate (62 mg, 0.755 mmol) in acetic acid (5 mL) was added bromine (90mg, 0.563 mmol) in acetic acid (1 mL). The resulting mixture was stirredat room temperature for 3 h, quenched by addition of saturated aqueoussodium bisulfate, and concentrated under vacuum. To the residue wasadded water (30 mL), and the mixture was adjusted to pH 7-8 withsaturated sodium bicarbonate and extracted with ethyl acetate (40 mL×2).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:10-1:1) to afford(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(4) (48 mg) with 44.9% yield. ¹H NMR (DMSO-d6, 300 MHz) δ 9.19 (d, J=6.9Hz, 1H), 7.87 (s, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.63-7.58 (m, 1H),7.22-7.17 (m, 1H), 2.44 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). MS(EI, m/z): 422.9 [M+H]⁺.

Example 2: Synthesis of(2-ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone(5)

A mixture of compound 3 (556 mg, 2.09 mmol), sodium acetate (367 mg,4.58 mmol) and iodine (1.17 g, 4.61 mmol) in methanol (20 mL) wasstirred under reflux for 1 h. Then a solution of sodium hydroxide (151mg, 3.78 mmol) in water (20 mL) was added. The reaction mixture wasstirred under reflux for 1 h and cooled to room temperature. Saturatedaqueous sodium bisulfate (20 mL) was added. The precipitates formed werecollected by filtration, washed with water, and dried. The crude productwas crystallized from petroleum ether/ethyl acetate to give(2-ethylimidazo[1,2-a]-pyridine-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone(5) (924 mg) with 85.3% yield. ¹H NMR (DMSO-d6, 300 MHz) δ 9.17 (d,J=6.9 Hz, 1H), 8.05 (s, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.64-7.58 (m, 1H),7.22-7.17 (m, 1H), 2.45 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). MS(EI, m/z): 518.8 [M+H]⁺.

Example 3: Synthesis of(3-chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone(8) and(3-chloro-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]-pyridin-3-yl)methanone(9)

Step A: A solution of 2-bromoacetyl bromide (6.8 g, 33.7 mmol) inanhydrous dichloromethane (10 mL) was added dropwise into a mixture of1-chloro-2-methoxybenzene (4.0 g, 28.1 mmol) and aluminum chloride (4.12g, 30.9 mmol) in anhydrous dichloromethane (30 mL) in an ice bath. Afteraddition, the reaction mixture was stirred for another 1.5 h and pouredinto ice-water (100 mL). The mixture was extracted with dichloromethane(60 mL×3). The combined organic layer was washed with water (30 mL),saturated sodium bicarbonate (30 mL×2), water (30 mL) and brine (30 mL),dried over anhydrous sodium sulfate, filtered through a short silica gelpad, and concentrated under vacuum. The residue was recrystallized withpetroleum ether/dichloromethane to get2-bormo-1-(3-chloro-4-methoxyphenyl)ethanone (6) (3.37 g) with 45.5%yield.

Step B: A mixture of compound 1 (780 mg, 5.23 mmol) and compound 6 (1.37g, 5.20 mmol) in toluene (20 mL) was stirred under reflux for 24 h andcooled to room temperature. After addition of water (50 mL), thereaction mixture was adjusted to pH 8-9 with saturated potassiumcarbonate and extracted with dichloromethane (60 mL×3). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:20-1:5) to afford(3-chloro-4-methoxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(7) (510 mg) with 31.2% yield.

Step C: Boron tribromide (3.2 mL, 1.0 M in toluene) was added dropwiseinto a mixture of compound 7 (500 mg, 1.57 mmol) in anhydrousdichloromethane (15 mL) in an ice-water bath. The reaction mixture wasstirred at room temperature overnight, poured into ice-water (40 mL),adjusted to pH 7-8 with saturated sodium bicarbonate, and extracted withethyl acetate (40 mL×2). The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by flash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:5-3:1) to afford(3-chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]-pyridine-3-yl)methanone(8) (380 mg) with 79.5% yield. MS (EI, m/z): 301.7 [M+H]⁺.

Step D: A mixture of compound 8 (378 mg, 1.26 mmol), sodium acetate (114mg, 1.39 mmol) and iodine (351 mg, 1.38 mmol) in methanol (30 mL) wasstirred under reflux for 1 h. After adding a solution of sodiumhydroxide (45 mg, 1.13 mmol) into water (13 mL), the reaction mixturewas stirred under reflux for 1 h and cooled to room temperature.Saturated aqueous sodium bisulfate (30 mL) was added. The precipitateswere collected by filtration, washed with water, and dried. The crudeproduct was recrystallized with petroleum ether/ethyl acetate to afford(3-chloro-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(9) (430 mg) with 85.3% yield. ¹H NMR (DMSO-d6, 500 MHz) δ 9.04 (d,J=7.0 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.71-7.68 (m, 2H), 7.54-7.51 (m,1H), 7.13-7.10 (m, 1H), 2.49-2.47 (m, 2H), 1.18 (t, J=7.5 Hz, 3H). MS(EI, m/z): 426.9 [M+H]⁺.

Example 4: Synthesis of3-chloro-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile(10)

A mixture of compound 9 (393 mg, 0.921 mmol) and cuprous cyanide (124mg, 1.38 mmol) in DMF (5 mL) was stirred at 130° C. overnight, cooled toroom temperature, diluted with water (30 mL), and extracted with ethylacetate (30 mL×3). The combined organic layer was washed with water (20mL×2) and brine (10 mL), dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=2:1-5:1) to afford3-chloro-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile(10). ¹H NMR (DMSO-d6, 300 MHz) δ 9.11 (d, J=6.3 Hz, 1H), 7.94-7.90 (m,2H), 7.80-7.77 (m, 1H), 7.68-7.63 (m, 1H), 7.26-7.21 (m, 1H), 2.50-2.48(m, 2H), 1.17 (t, J=7.2 Hz, 3H). MS (EI, m/z): 324.0 [M−H]⁻.

Example 5: Synthesis of(3-bromo-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]-pyridine-3-yl)methanone(11)

Compound 11 was prepared according to the procedure of example 3 byusing 1-bromo-2-methoxybenzene in step A as an alternative reagent. ¹HNMR (DMSO-d6, 300 MHz) δ 9.16 (d, J=6.9 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H),7.87 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.62-7.56 (m, 1H),7.20-7.16 (m, 1H), 2.43 (t, J=7.5 Hz, 2H), 1.18 (t, J=7.5 Hz, 3H). MS(EI, m/z): 470.9 [M+H]⁺.

Example 6: Synthesis of(2-ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-iodo-5-methylphenyl)methanone(12)

Compound 12 was prepared according to the procedure of example 3 byusing 1-methoxy-2-methylbenzene in step A as an alternative reagent. ¹HNMR (DMSO-d6, 300 MHz)

9.91 (s, 1H), 9.14 (dd, J=0.9, 6.9 Hz, 1H), 7.88 (s, 1H), 7.74-7.71 (m,1H), 7.59-7.51 (m, 2H), 7.18-7.13 (m, 1H), 2.44 (t, J=7.5 Hz, 2H), 2.30(s, 3H), 1.17 (t, J=7.5 Hz, 3H). MS (EI, m/z): 406.9 [M+H]⁺.

Example 7: Synthesis of(2-ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-iodophenyl)-methanone(13)

Compound 13 was prepared according to the procedures of steps A, B and Cin example 3 by using 1-iodo-2-methoxybenzene as an alternative reagent.¹H NMR (DMSO-d6, 500 MHz) δ 11.16 (s, 1H), 9.13 (d, J=7.0 Hz, 1H), 8.02(d, J=1.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.61 (dd, J=2.0, 8.0 Hz, 1H),7.57-7.54 (m, 1H), 7.16-7.13 (m, 1H), 7.01 (d, J=8.5 Hz, 1H), 2.45 (q,J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H). MS (EI, m/z): 392.9 [M+H]⁺.

Example 8: Synthesis of5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (14)

Using compound 13 as the starting material, compound 14 was preparedaccording to the procedure of example 4. ¹H NMR (DMSO-d6, 500 MHz) δ11.91 (s, 1H), 9.19 (d, J=6.5 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.85 (dd,J=2.0, 8.5 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.19-7.15(m, 2H), 2.43 (q, J=7.5 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H). MS (EI, m/z):292.0 [M+H]⁺.

Example 9: Synthesis of(3-bromo-5-chloro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone(18)

Step A: To a mixture of 2-amino-5-fluoropyridine (2.5 g, 22.3 mmol) andtriethylamine (2.71 g, 26.8 mmol) in anhydrous dichloromethane (25 mL)was added propionyl chloride (2.17 g, 23.5 mmol) dropwise in anice-water bath. After addition, the reaction mixture was stirred at roomtemperature overnight, quenched with water (40 mL), and extracted withdichloromethane (40 mL×3). The combined organic layer was washed withbrine (30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:5) to afford N-(5-fluoropyridine-2-yl)propionamide (15) (3.04 g)with 81.1% yield.

Step B: A mixture of compound 15 (960 mg, 5.71 mmol) and compound 6 (1.5g, 5.69 mmol) in toluene (30 mL) was stirred under reflux overnight,cooled to room temperature, diluted with water (30 mL), adjusted to pH8-9 with saturated potassium carbonate, and extracted withdichloromethane (40 mL×3). The combined organic layer was washed withwater, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by flash column chromatography onsilica gel (eluted with ethyl acetate/petroleum ether=1:30-1:1) toafford(3-chloro-4-methoxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(16) (270 mg) with 14.3% yield.

Step C: A 1.0 M solution of boron tribromide in toluene (2.4 mL) wasadded dropwise into a mixture of compound 16 (262 mg, 0.787 mmol) inanhydrous dichloromethane (10 mL) in an ice-water bath. The reactionmixture was stirred at room temperature for 6 h, diluted with ice-water(30 mL), adjusted to pH 7-8 with saturated sodium bicarbonate, andextracted with ethyl acetate (40 mL×3). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by flash column chromatography on silica gel(eluted with ethyl acetate/petroleum ether=1:6-1:4) to afford(3-chloro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanone(17) (90 mg) with 35.9% yield. MS (EI, m/z): 339.7 [M+H]⁺.

Step D: To a mixture of compound 17 (41 mg, 0.129 mmol) and sodiumacetate (26 mg, 0.317 mmol) in acetic acid (5 mL) was added bromine (25mg, 0.156 mmol) in acetic acid (1 mL). The resulting mixture was stirredat room temperature for 1.5 h, quenched by saturated aqueous sodiumbisulfate, and then concentrated under vacuum. To the residue was addedwater (20 mL), and the mixture was adjusted to pH 7-8 with saturatedsodium bicarbonate and extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:6-1:3) to afford(3-bromo-5-chloro-4-hydroxyphenyl)-(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone(18). ¹H NMR (DMSO-d6, 500 MHz) δ 11.06 (s, 1H), 9.22-9.21 (m, 1H),7.86-7.83 (m, 2H), 7.76-7.70 (m, 2H), 2.43 (q, J=7.5 Hz, 2H), 1.16 (t,J=7.5 Hz, 3H). MS (EI, m/z): 398.9 [M+H]⁺.

Example 10: Synthesis of(3-chloro-4-hydroxy-5-iodophenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone(19)

A mixture of compound 17 (41 mg, 0.129 mmol), sodium acetate (12 mg,0.146 mmol) and iodine (36 mg, 0.142 mmol) in methanol (10 mL) wasstirred under reflux for 1 h, and then a solution of sodium hydroxide (5mg, 0.125 mmol) in water (3 mL) was added. The reaction mixture wasstirred under reflux for 1 h, cooled to room temperature, and addedsaturated aqueous sodium bisulfate (10 mL). The precipitates formed werecollected by filtration, washed with water and dried. The crude productwas crystallized with petroleum ether/ethyl acetate to get(3-chloro-4-hydroxy-5-iodophenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone(19). ¹H NMR (DMSO-d6, 500 MHz) δ 9.13 (s, 1H), 7.97 (d, J=2.0 Hz, 1H),7.83-7.80 (m, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.69-7.65 (m, 1H), 2.46 (q,J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). MS (EI, m/z): 444.9 [M+H]⁺.

Example 11: Synthesis of5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-methylbenzonitrile(24)

Step A: A mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (4.95 g, 33.0mmol), sodium acetate (2.98 g, 36.3 mmol) and iodine (9.21 g, 36.3 mmol)in methanol (80 mL) was stirred under reflux for 1 h, and then asolution of sodium hydroxide (1.19 g, 29.7 mmol) in water (55 mL) wasadded. The reaction mixture was stirred under reflux for 1 h andevaporated to about half of the volume under vacuum. The precipitatesformed were collected by filtration. The cake was dissolved into ethylacetate (200 mL), and the solution was washed with saturated aqueoussodium bisulfate (40 mL) and brine (40 mL), dried over anhydrous sodiumsulfate and concentrated to give1-(4-hydroxy-3-iodo-5-methylphenyl)ethanone (21) (7.91 g) with 86.8%yield.

Step B: A mixture of compound 21 (3.90 g, 14.1 mmol) and cuprous cyanide(1.90 g, 21.2 mmol) in DMF (25 mL) was stirred at 130° C. overnight. Thereaction mixture was cooled to room temperature and filtered through acelite pad. To the filtrate was added water (100 mL). The mixture wasextracted with ethyl acetate (50 mL×3). The combined organic layer waswashed with water (30 mL×2) and brine (30 mL), dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby flash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:15-1:3) to afford5-acetyl-2-hydroxy-3-methyl-benzonitrile (22) (2.07 g) with 83.8% yield.

Step C: To a solution of compound 22 (500 mg, 2.85 mmol) in methanol (10mL) was added bromine (548 mg, 3.43 mmol) in methanol (4 mL), and thereaction mixture was stirred at room temperature for 6 h. After additionof water (50 mL), the resulting mixture was extracted with ethyl acetate(40 mL×3). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, and concentrated under vacuum toafford 5-(2-bromoacetyl)-2-hydroxy-3-methylbenzonitrile (23) (800 mg).The crude product 23 was used directly in the next step without furtherpurification.

Step D: A mixture of crude compound 23 (800 mg) and compound 1 (600 mg,3.99 mmol) in toluene (15 mL) was stirred under reflux overnight andcooled to room temperature. To the reaction mixture was added methanol(15 mL) and potassium carbonate (1.10 g, 8.0 mmol). The resultingmixture was stirred at room temperature for 30 minutes, diluted withwater (40 mL), and extracted with ethyl acetate (50 mL×3). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by flash column chromatography onsilica gel (eluted with ethyl acetate/petroleum ether=1:30-1:1) toafford5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-methylbenzonitrile(24). ¹H NMR (DMSO-d6, 300 MHz) δ 10.99 (s, 1H), 9.15 (d, J=6.9 Hz, 1H),7.79 (s, 1H), 7.74-7.72 (m, 2H), 7.60-7.55 (m, 1H), 7.19-7.14 (m, 1H),2.43 (q, J=7.5 Hz, 2H), 2.26 (s, 3H), 1.14 (t, J=7.5 Hz, 3H). MS (EI,m/z): 306.1 [M+H]⁺.

Example 12: Synthesis of(2-thylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-(trifluoro-methyl)phenyl)methanone(28) and(3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl)-(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(29)

Step A: A mixture of 1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (1.0g, 4.85 mmol) and sodium methoxide (288 mg, 5.33 mmol) in DMF (5 mL) wasstirred for 2 h in an ice-water bath and then at room temperatureovernight. The reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (30 mL×3). The combined organic layer waswashed with brine (20 mL), dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:40) to get 1-(4-methoxy-3-(trifluoromethyl)phenyl)ethanone (25)(950 mg) with 89.8% yield.

Steps B and C were followed the methods used in steps C and D of example11.

Step D: Sodium hydride (60% in mineral oil, 69 mg, 1.73 mmol) was addedportionwise to a solution of ethanethiol (107 mg, 1.73 mmol) in DMF (5mL), and the mixture was stirred for about 5 minutes at roomtemperature. A solution of compound 27 (200 mg, 0.574 mmol) in DMF (3mL) was added into the above mixture. The reaction mixture was stirredat 120° C. for 2 h, cooled to room temperature, and diluted with water(40 mL). The mixture was adjusted to pH 8-9 with 2 M hydrochloric acidand extracted with ethyl acetate (40 mL×3). The combined organic layerwas washed with water (30 mL) and brine (20 mL), dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby flash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:1) to give(2-ethylimidazo[1,2-a]pyridine-3-yl)-(4-hydroxy-3-(trifluoromethyl)phenyl)methanone(28) (120 mg) with 62.6% yield. ¹H NMR (DMSO-d6, 300 MHz) δ 11.55 (s,1H), 9.17 (d, J=6.9 Hz, 1H), 7.86 (d, J=6.0 Hz, 2H), 7.75 (d, J=9.0 Hz,1H), 7.63-7.57 (m, 1H), 7.21-7.16 (m, 1H), 2.43 (q, J=7.5 Hz, 2H), 1.15(t, J=7.5 Hz, 3H). MS (EI, m/z): 335.1 [M+H]⁺.

Step E: To a mixture of compound 28 (96 mg, 0.287 mmol) and sodiumacetate (59 mg, 0.719 mmol) in acetic acid (5 mL) was added bromine (55mg, 0.719 mmol) in acetic acid (1 mL). The resulting mixture was stirredat room temperature for 1.5 h, quenched by addition of saturated aqueoussodium bisulfate, concentrated under vacuum, and then diluted with water(20 mL). The mixture was adjusted to pH 7-8 with saturated sodiumbicarbonate, extracted with ethyl acetate (40 mL×2), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by flash column chromatography on silica gel(eluted with ethyl acetate/petroleum ether=1:5-3:2) to afford(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)-methanone(29)(85 mg) with 71.9% yield. ¹H NMR (DMSO-d6, 500 MHz) δ 9.19 (d, J=6.5Hz, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.66-7.62(m, 1H), 7.24-7.21 (m, 1H), 2.41 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz,3H). MS (EI, m/z): 413.0 [M+H]⁺.

Example 13: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methylimidazo[1,2-a]pyridine-3-yl)methanone(30)

Compound 30 was prepared according to the procedure of example 1 byusing 5-methylpyridin-2-amine as an alternative reagent in step A. ¹HNMR (DMSO-d6, 500 MHz) δ 9.04 (s, 1H), 7.87 (s, 2H), 7.69 (d, J=9.0 Hz,1H), 7.52 (d, J=9.0 Hz, 1H), 2.42-2.38 (m, 5H), 1.15 (t, J=7.5 Hz, 3H).MS (EI, m/z): 436.9 [M−H]⁻.

Example 14: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methoxyimidazo[1,2-a]pyridine-3-yl)methanone(33)

Step A: To a mixture of 2-bromo-1-(4-hydroxyphenyl)ethanone (639 mg,2.98 mmol) and sodium acetate (740 mg, 9.02 mmol) in acetic acid (10 mL)was added bromine (960 mg, 6.0 mmol) in acetic acid (5 mL), and theresulting mixture was stirred at room temperature for 10 minutes. Afteraddition of water (40 mL), the precipitates formed were collected byfiltration, washed with water, and dried to give2-bromo-1-(3,5-dibromo-4-hydroxyphenyl)ethanone (31) (890 mg) with 80.1%yield.

Step B: To a mixture of 5-methoxypyridin-2-amine (1.0 g, 8.05 mmol) andtriethylamine (981 mg, 9.69 mmol) in dichloromethane (8 mL) was addedpropionyl chloride (777 mg, 8.4 mmol) dropwise in an ice-water bath.After addition, the reaction mixture was warmed to room temperature andstirred overnight. To the reaction mixture was added water (40 mL), andthe mixture was extracted with dichloromethane (30 mL×3). The combinedorganic layer was washed with brine (30 mL), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified byflash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:30-1:8). The product was recyrstallized withpetroleum ether to afford N-(5-methoxypyridine-2-yl)-propionamide (32)(349 mg) with 21.4% yield.

Step C: A mixture of compound 31 (790 mg, 2.12 mmol) and compound 32(340 mg, 1.89 mmol) in toluene (20 mL) was stirred under reflux for 48 hand cooled to room temperature. To the mixture was added water (50 mL),and the resulting mixture was adjusted to pH 8-9 with saturatedpotassium carbonate and extracted with dichloromethane (50 mL×3). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:10-2:5) to afford (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methoxyimidazo[1,2-a]pyridine-3-yl)methanone (33) (87 mg)with 10.1% yield. ¹H NMR (DMSO-d6, 500 MHz) δ 8.71 (s, 1H), 7.79 (s,2H), 7.64 (d, J=10.0 Hz, 1H), 7.34 (d, J=10.0 Hz, 1H), 3.81 (s, 3H),2.45 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H). MS (EI, m/z): 452.9[M−H]⁻.

Example 15: Synthesis of3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile(38)

Step A: 1-(4-Methoxyphenyl)ethanone (44 g, 293 mmol) was added into amixture of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]ocatanebis(tetrafluoroborate) (104 g, 294 mmol) and iodine (38.6 g, 152 mmol)in acetonitrile (440 mL) in an ice-water bath. The reaction mixture waswarmed to room temperature and stirred overnight. To the mixture wasadded water (1350 mL). The precipitates formed were collected byfiltration, washed with water and dried to give1-(3-iodo-4-methoxyphenyl)ethanone (34) (70 g) with 86.5% yield.

Step B: A mixture of compound 34 (70.0 g, 254 mmol) and cuprous cyanide(34.0 g, 380 mmol) in DMF (400 mL) was stirred at 130° C. overnight. Thereaction mixture was cooled to room temperature and filtered through acelite pad. To the filtrate was added water (1600 mL), and the mixturewas extracted with ethyl acetate (800 mL×3). The combined organic layerwas washed with water (40 mL×2) and brine (400 mL), dried over anhydroussodium sulfate, filtered, and concentrated under vacuum to give5-acetyl-2-methoxybenzonitrile (35) (50.0 g). The crude product was useddirectly in the next step without further purification.

Step C: To a solution of crude compound 35 (45.0 g) in methanol (250 mL)was added bromine (49.0 g, 307 mmol) in methanol (50 mL), and theresulting mixture was stirred at room temperature overnight. To themixture was added water (900 mL) and the precipitate were collected byfiltration, washed with water and dried to give5-(2-bromoacetyl)-2-methoxybenzonitrile (36) (41.0 g). The total yieldof steps B and C was 70.6%.

Step D: A mixture of compound 36 (41.0 g, 161 mmol) and compound 1 (24.0g, 161 mmol) in toluene (600 mL) was stirred at reflux for 48 h. Thereaction mixture was cooled to room temperature, diluted with water (400mL), adjusted to pH 7-8 with saturated sodium bicarbonate, and extractedwith dichloromethane (600 mL×3). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by flash column chromatography on silica gel (eluted withethyl acetate/petroleum ether=1:30-2:1) to afford5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-methoxybenzonitrile (37)(25.7 g) with 52.3% yield.

Step E: Sodium hydride (60% dispersion in mineral oil, 4.8 g, 120 mmol)was added portionwise to a solution of ethanethiol (8.4 mL) in THF (30mL). The reaction mixture was stirred for about 5 minutes and filtered.The cake was added into a solution of compound 37 (9.0 g, 29.5 mmol) inDMF (25 mL). The resulting mixture was stirred at 60° C. for 2 h, cooledto room temperature, and filtered through a celite pad. To the filtratewas added water (100 mL), and the mixture was adjusted to pH 5-6 with 2M aqueous citric acid. The precipitates formed were collected byfiltration, washed with water, and dried. The cake was crystallized fromacetonitrile to give5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (14)(7.2 g) with 83.8% yield.

Step F: To a solution of compound 14 (7.2 g, 24.7 mmol) in DMF (70 mL)was added N-bromosuccimide (5.28 g, 29.7 mmol) portionwise. Afteraddition, the reaction mixture was stirred for another 1 h and dilutedwith water (210 mL). The precipitates were collected by filtration,washed with water and dried. The cake was crystallized from acetonitrileto give3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile(38) (7.0 g) with 76.8% yield. ¹H NMR (DMSO-d6, 300 MHz) δ 9.01 (d,J=6.9 Hz, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.78-7.75 (m, 1H), 7.65-7.59(m, 1H), 7.22-7.17 (m, 1H), 2.58-2.50 (m, 2H), 1.19 (t, J=7.2 Hz, 3H).MS (EI, m/z): 368.0 [M−H]⁻.

Example 16: Synthesis of5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile(39)

Using compound 14 as a starting material, compound 39 was preparedaccording to the procedure of example 10. ¹H NMR (DMSO-d6, 500 MHz) δ9.04 (d, J=7.0 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.87 (s, 1H), 7.77 (d,J=8.5 Hz, 1H), 7.66-7.63 (m, 1H), 7.23-7.21 (m, 1H), 2.56-2.50 (m, 2H),1.20 (t, J=7.5 Hz, 3H). MS (EI, m/z): 416.0 [M−H]⁻.

Example 17: Synthesis of5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-3-fluoro-2-hydroxybenzonitrile(40)

Compound 40 was prepared according to the procedures of steps A, B and Cin example 11 and step C in example 14 by using1-(3-fluoro-4-hydroxyphenyl)ethanone as an alternative reagent. ¹H NMR(DMSO-d6, 300 MHz) δ 9.18 (d, J=6.9 Hz, 1H), 7.83-7.75 (m, 3H),7.64-7.59 (m, 1H), 7.23-7.18 (m, 1H), 2.46-2.41 (m, 2H), 1.15 (t, J=7.2Hz, 3H). MS (EI, m/z): 310.1[M+H]⁺.

Example 18: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-propylimidazo[1,2-a]-pyridine-3-yl)methanone(41)

Compound 41 was prepared according to the procedure of example 1 byusing butyryl chloride in step A. ¹H NMR (DMSO-d6, 500 MHz) δ 10.81 (s,1H), 9.18 (d, J=6.5 Hz, 1H), 7.86 (s, 2H), 7.73 (d, J=9.0 Hz, 1H),7.61-7.58 (m, 1H), 7.19-7.17 (m, 1H), 2.38 (q, J=7.5 Hz, 2H), 1.68-1.63(m, 2H), 0.76 (t, J=7.5 Hz, 3H). MS (EI, m/z): 436.9 [M−H]⁻.

Example 19: Synthesis of(2-ethylimidazo[1,2-a]pyridine-3-yl)(2-ethylsulfanyl-4-hydroxyphenyl)methanone(44)

Compound 44 was prepared according to the procedures of steps B, C and Din example 12 by using 1-(2-fluoro-4-methoxyphenyl)ethanone as analternative reagent. ¹H NMR (DMSO-d6, 500 MHz) δ 10.08 (s, 1H), 9.42 (d,J=7.0 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.63-7.59 (m, 1H), 7.27-7.20 (m,2H), 6.88 (d, J=2.0 Hz, 1H), 6.68 (dd, J=2.0, 8.0 Hz, 1H), 2.88 (q,J=7.5 Hz, 2H), 2.26 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H), 1.05 (t,J=7.5 Hz, 3H). MS (EI, m/z): 325.1 [M−H]⁻.

Example 20: Synthesis of(3-bromo-5-chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]-pyridin-3-yl)methanone(45)

Using compound 8 as a starting material, compound 45 was preparedaccording to the procedure of step D in example 9. ¹H NMR (DMSO-d6, 500MHz) δ 9.19 (d, J=6.5 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.76-7.74 (m,2H), 7.61-7.58 (m, 1H), 7.20-7.17 (m, 1H), 2.43 (q, J=7.5 Hz, 2H), 1.16(t, J=7.5 Hz, 3H). MS (EI, m/z): 379.0 [M−H]⁻.

Example 21: Synthesis of(3-bromo-5-fluoro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo-[1,2-a]pyridin-3-yl)methanone(48)

Step A: To a solution of 1-(3-fluoro-4-hydroxyphenyl)ethanone (806 mg,5.23 mmol) in DMF (10 mL) was added N-bromosuccimide (977 mg, 5.49 mmol)portionwise. After addition, the reaction mixture was stirred foranother 1 h. Water (50 mL) was added and the mixture was extracted withethyl acetate (50 mL×3). The combined organic layer was washed withwater (30 mL×3) and brine (20 mL), dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was crystallized frompetroleum ether/ethyl acetate to get1-(3-bromo-5-fluoro-4-hydroxy-phenyl)ethanone (46) (1.0 g) with 82.0%yield.

Step B: To a solution of compound 46 (1.0 g, 4.29 mmol) in methanol (20mL) was added bromine (824 mg, 5.16 mmol) in methanol (5 mL), and themixture was stirred at room temperature overnight, quenched with water(60 mL), and extracted with ethyl acetate (60 mL×3). The combinedorganic layer was washed with brine (30 mL), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified by flashcolumn chromatography on silica gel (eluted with ethyl acetate/petroleumether=1:5) to afford2-bromo-1-(3-bromo-5-fluoro-4-hydroxyphenyl)-ethanone (47) (940 mg) with70.2% yield.

Step C: A mixture of compound 15 (210 mg, 1.25 mmol) and compound 47(300 mg, 0.962 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was stirred at150° C. overnight. The reaction mixture was cooled to room temperatureand water (50 mL) was added. The mixture was adjusted to pH 7-8 with 2 Maqueous citric acid and extracted with dichloromethane (50 mL×3). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flash columnchromatography on silica gel (eluted with ethyl acetate/petroleumether=1:25-1:5) to afford(3-bromo-5-fluoro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]-pyridin-3-yl)methanone(48). ¹H NMR (DMSO-d6, 500 MHz) δ 11.44 (s, 1H), 9.24-9.22 (m, 1H),7.88-7.85 (m, 1H), 7.75-7.71 (m, 2H), 7.63-7.60 (m, 1H), 2.47 (q, J=7.5Hz, 2H), 1.18 (t, J=7.5 Hz, 3H). MS (EI, m/z): 379.0 [M−H]⁻.

Example 22: Synthesis of(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)(3-fluoro-4-hydroxy-5-iodophenyl)methanone(51)

Using compound 15 as the starting material, compound 51 was preparedaccording to the procedures of steps B and C in example 9, followed bythe procedure in example 10. ¹H NMR (DMSO-d6, 300 MHz) δ 11.44 (s, 1H),9.19-9.17 (m, 1H), 7.86-7.81 (m, 2H), 7.73-7.66 (m, 1H), 7.60-7.56 (m,1H), 2.49-2.41 (m, 2H), 1.16 (t, J=7.5 Hz, 3H). MS (EI, m/z): 427.1[M−H]⁻.

Example 23: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxyimidazo-[1,2-a]pyridin-3-yl)methanone(52)

Using compound 33 as the starting material, compound 52 was preparedaccording to the procedure of step C in example 1. ¹H NMR (DMSO-d6, 400MHz) δ 10.00 (s, 1H), 8.92 (s, 1H), 7.84 (s, 2H), 7.63 (d, J=9.6 Hz,1H), 7.31-7.29 (m, 1H), 2.37 (q, J=7.6 Hz, 2H), 1.13 (t, J=7.6 Hz, 3H).MS (EI, m/z): 441.0 [M+H]⁺.

Example 24: Synthesis of(6-bromo-2-ethyl-7-methylimidazo[1,2-a]pyridin-3-yl)-(3,5-dibromo-4-hydroxyphenyl)methanone(56)

Step A: Sodium hydride (60% dispersion in mineral oil, 1.68 g, 42 mmol)was added portionwise to a solution of 1-(4-methoxyphenyl)ethanone (3.0g, 20.0 mmol) in DMF (15 mL) at −10-0° C. The mixture was stirred atthis temperature for another 40 minutes, and ethyl propionate was added(2.04 g, 20 mmol). The reaction mixture was stirred at room temperatureovernight, diluted with water (60 mL), and extracted with ethyl acetate(30 mL×3). The combined organic layer was washed with brine (20 mL×2),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash column chromatography on silica gel(eluted with ethyl acetate/petroleum ether=1:30) to get1-(4-methoxyphenyl)pentane-1,3-dione (53) (3.16 g) with 76.6% yield.

Step B: To a solution of 5-bromo-4-methylpyridin-2-amine (187 mg, 1.0mmol) and compound 53 (247 mg, 1.2 mmol) in THF (6 mL) was added(diacetoxyiodo)benzene (386 mg, 1.2 mmol) and boron trifluoride ether(28 mg, 0.2 mmol) in an ice-water bath. After addition, the reactionmixture was stirred at room temperature overnight and diluted with water(30 mL). The mixture was adjusted to pH 7-8 with saturated sodiumbicarbonate and extracted with ethyl acetate (30 mL×3). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified by flashcolumn chromatography on silica gel (eluted with ethyl acetate/petroleumether=1:30) to get(6-bromo-2-ethyl-7-methylimidazo-[1,2-a]pyridin-3-yl)(4-methoxyphenyl)methanone(54) (120 mg) with 32.2% yield.

Methods used in steps C and D of example 1 were followed in steps C andD to afford(6-bromo-2-ethyl-7-methylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone(56). ¹H NMR (DMSO-d6, 400 MHz) δ 9.35 (s, 1H), 7.86 (s, 2H), 7.80 (s,1H), 2.41 (q, J=7.6 Hz, 2H), 1.16 (t, J=7.6 Hz, 3H). MS (EI, m/z): 518.9[M+H]⁺.

Example 25: Synthesis of(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-(trifluoromethyl)-imidazo[1,2-a]pyridin-3-yl)methanone(57)

Using 5-(trifluoromethyl)pyridin-2-amine as the starting material,compound 57 was prepared according to the procedure of step B in example25 and the procedures of steps C and D in example 1. ¹H NMR (DMSO-d6,400 MHz) δ 9.23 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 7.93 (s, 2H), 7.45 (dd,J=2.0, 7.2 Hz, 1H), 2.50-2.48 (m, 2H), 1.20 (t, J=7.2 Hz, 3H). MS (EI,m/z): 492.9 [M+H]⁺.

Example 26: Synthesis of3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylimidazo[1,2-a]-pyridine-6-carbonitrile(58)

Using 6-aminonicotinonitrile as the starting material, compound 58 wasprepared according to the procedure of step B in example 25 and theprocedures of steps C and D in example 1. ¹H NMR (DMSO-d6, 400 MHz) δ9.56-9.55 (m, 1H), 7.92-7.89 (m, 3H), 7.86-7.83 (m, 1H), 2.48-2.46 (m,2H), 1.22-1.17 (m, 3H). MS (EI, m/z): 450.0 [M+H]⁺.

Example 27: Synthesis of(2-deuterium-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]-pyridine-3-yl)methanone(62) and(2-deuterium-3,5-dibromo-4-hydroxyphenyl)-(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(63)

Step A: To a mixture of 1-(2-bromo-4-methoxyphenyl)ethanone (1.28 g,5.59 mmol) and deuteroxide (0.5 mL) in DMF (10 mL) was added palladiumon activated carbon (5%, 100 mg). After exchanged with deuterium gas,the reaction mixture was stirred under deuterium gas from a deuteriumgas balloon overnight and filtered through a celite pad. To the filtratewas added water (40 mL), and the mixture extracted with ethyl acetate(30 mL×2). The combined organic layer was washed with water (10 mL×4),dried over anhydrous sodium sulfate, concentrated under vacuum to give1-(2-deuterium-4-methoxyphenyl)ethanone (59)(910 mg) with 100% yield.

Method used in step C of example 15 was followed in step B to affordcompound 60.

Methods described in steps B, C and D in example 1 were followed insteps C, D and E to give(2-deuterium-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone(62) and (2-deuterium-3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone (63). Compound 62: ¹H NMR(DMSO-d6, 400 MHz) δ 11.20 (s, 1H), 9.16 (d, J=6.8 Hz, 1H), 7.85 (s,1H), 7.74 (d, J=8.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.19-7.15 (m, 1H),7.11-7.09 (m, 1H), 2.46 (q, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H). MS(EI, m/z): 268.2 [M+H]⁺. Compound 63: ¹H NMR (DMSO-d6, 400 MHz) δ 9.19(d, J=6.8 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.63-7.59 (m,1H), 7.21-7.18 (m, 1H), 2.44 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).MS (EI, m/z): 426.0 [M+H]⁺.

Example 28: Synthesis of(6-deuterium-2-ethylimidazo[1,2-a]pyridine-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone(69)

Step A: A mixture of 5-bromopyridin-2-amine (5.19 g, 30.0 mmol),ethyldiisopropylamine (8.58 g, 66.4 mmol), 4-dimethylaminopyridine (366mg, 3.0 mmol) and di-tert-butyl dicarbonate (14.4 g, 66.0 mmol) indichloromethane (30 mL) was stirred at room temperature overnight. Thereaction mixture was concentrated under vacuum. The residue was purifiedby flash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:20-1:3) to get imidodicarbonic acid(2-(4-bromo-2-pyridinyl)-1,3-bis(1,1-dimethylethyl))ester (64) (5.38 g)with 48.0% yield.

Step B: To a mixture of compound 64 (5.59 g, 15.0 mmol), DMF (25 mL) anddeuteroxide (0.5 mL) was added palladium on activated carbon (5%, 200mg). After exchanged with deuterium gas, the mixture was stirred underdeuterium gas from a balloon for 48 h. The reaction mixture was filteredthrough a celite pad. To the filtrate was added water (100 mL), and themixture extracted with ethyl acetate (50 mL×3). The combined organiclayer was washed with water (30 mL×3), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified byflash column chromatography on silica gel (eluted with ethylacetate/petroleum ether=1:40-1:1) to get imidodicarbonic acid(2-(4-deuterium-2-pyridinyl)-1,3-bis(1,1-dimethylethyl))ester (65) (2.70g) with 60.9% yield.

Step C: A mixture of compound 65 (2.69 g, 9.11 mmol), trifluoroaceticacid (4 mL) and water (0.5 mL) in dichloromethane (20 mL) was stirred atroom temperature overnight. To the reaction mixture was added water (30mL), and the mixture was adjusted pH 8-9 with 2 M aqueous sodiumhydroxide and extracted with ethyl acetate (40 mL×3). The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash column chromatography onsilica gel (eluted with ethyl acetate/petroleum ether=1:10-1:1) to get2-amino-4-deuterium-pyridine (66) (676 mg) with 78.0% yield.

Methods described in steps B, C and D in example 25 were followed insteps D, E and F the to give(6-deuterium-2-ethylimidazo[1,2-a]pyridine-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone(69). ¹H NMR (DMSO-d6, 400 MHz) δ 9.20-9.19 (m, 1H), 7.88 (s, 2H),7.77-7.75 (m, 1H), 7.64-7.59 (m, 1H), 2.43 (q, J=7.6 Hz, 2H), 1.16 (t,J=7.6 Hz, 3H). MS (EI, m/z): 426.0 [M+H]⁺.

Example 29: Synthesis of(2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone(73)

Using ethyl cyclopropanecarboxylate as the starting material, compound71 was prepared according to the procedures of steps A and B in example24. ¹H NMR (DMSO-d6, 400 MHz) δ9.24-9.23 (m, 1H), 7.81-7.79 (m, 2H),7.68-7.65 (m, 1H), 7.58-7.56 (m, 1H), 7.16-7.09 (m, 3H), 3.87 (s, 3H),1.56-1.54 (m, 1H), 1.08-1.06 (m, 2H), 0.88-0.85 (m, 2H).

Method used in step E in example 15 was followed in step C to give(2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(4-hydroxyphenyl)methanone(72). ¹H NMR (DMSO-d6, 400 MHz) δ 9.17-9.16 (m, 1H), 7.72-7.70 (m, 2H),7.66-7.64 (m, 1H), 7.55-7.51 (m, 1H), 7.14-7.10 (m, 1H), 6.91-6.89 (m,2H), 1.62-1.60 (m, 1H), 1.07-1.05 (m, 2H), 0.88-0.85 (m, 2H).

Method used in step F of example 15 was followed in step D to give(2-cyclopropylimidazo-[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone(73). ¹H NMR (DMSO-d6, 400 MHz) δ 9.25-9.23 (m, 1H), 7.97 (s, 2H),7.70-7.68 (m, 1H), 7.61-7.57 (m, 1H), 7.20-7.16 (m, 1H), 1.58-1.55 (m,1H), 1.13-1.10 (m, 2H), 0.94-0.89 (m, 2H). MS (EI, m/z): 437.0 [M+H]⁺.

Example 30: Synthesis of3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrilehydrogen chloride (74)

A mixture of compound 38 (970 mg, 2.62 mmol) in ethyl acetate (200 mL)was stirred under reflux for 20 min to give a clear solution, thencooled to room temperature, bubbled with hydrogen chloride for about 5minutes. The precipitates formed were collected by filtration to give3-bromo-5-(2-ethylimidazo[1,2-a]-pyridine-3-carbonyl)-2-hydroxybenzonitrilehydrogen chloride (74) (794 mg) with 74.5% yield. ¹H NMR (DMSO-d6, 300MHz) δ 9.12 (d, J=6.9 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.1Hz, 1H), 7.99-7.91 (m, 2H), 7.50-7.45 (m, 1H), 2.57 (q, J=7.5 Hz, 2H),1.23 (t, J=7.5 Hz, 3H). MS (EI, m/z): 368.0 [M−H]⁻.

Example 31: Synthesis of5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrilehydrogen chloride (75)

Using compound 39 as the starting material, compound 75 was preparedfollowed the same procedure as example 30. ¹H NMR (DMSO-d6, 300 MHz) δ9.11 (d, J=6.9 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H),8.02-7.95 (m, 2H), 7.54-7.49 (m, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.25 (t,J=7.5 Hz, 3H). MS (EI, m/z): 416.0 [M−H]⁻.

Example 32: Inhibition assay of uric acid transport for compounds inHEK293-hURAT1 transfection cell line

1. Materials

Benzbromarone was purchased from Sigma-Aldrich Co. LLC. PlasmidpCMV6-hURAT1 was purchased from Origene Technologies, Inc. G418 waspurchased from Sangon Biotech (Shanghai) Co., Ltd. HEK293 cell line waspurchased from Cell Resource Center of Shanghai Institutes forBiological Sciences of the Chinese Academy of Sciences. ¹⁴C-Uric acidwas purchased from American Radiolabeled Chemicals, Inc. Sodiumgluconate, potassium gluconate, calcium gluconate, KH₂PO₄, MgSO₄,glucose, and HEPES were purchased from Sinopharm Chemical Reagent Co.,Ltd. DMEM culture medium and fetal bovine serum were purchased fromThermo Fisher Scientific Inc.

2. Experimental Methods

2.1 Construction of a HEK293 stable cell line with high expression ofhURAT1: The plasmid pCMV6-hURAT1 was transfected into HEK293 cells, thenthe stable strain was obtained by the G418 (final concentration 500μg/mL) resistance screening, which is the high expression of hURAT1transporter membrane protein. It can be used for in vitro inhibitionassay of uric acid transporter hURAT1. (Weaver Y M, Ehresman D J,Butenhoff J L, et al. Roles of rat renal organic anion transporters intransporting perfluorinated carboxylates with different chain lengths.Toxicological Sciences, 2009, 113(2):305-314)

2.2 To a coated 24-well plate was added 200 μL of 0.1 mg/mL poly-lysineper well and the plate was left overnight. Poly-lysine was removed fromwells. The wells were cleaned thoroughly with aseptic water and driedfor use.

2.3 To the above coated 24 well plate was added HEK293-hURAT1 stablecells (2×10⁵ cells per well). The cells was cultured at 37° C. under 5%CO₂ for 3 days.

2.4 The preparation of HBSS buffer: weighed following reagents accordingto the final concentration of 125 mM sodium gluconate, 4.8 mM potassiumgluconate, 1.3 mM calcium gluconate, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 5.6 mMglucose, and 25 mM HEPES with deionized water. The solution was fullymixed to give HBSS buffer (pH value: 7.4). The buffer was stored at −20°C.

2.5 The HBSS buffer was warmed to 37° C. in a water bath. Washed cellswith HBSS twice, added 160 μL of HBSS and 20 μL test compound per well.The final concentration of tested compound per well is 500 nM. The blankcontrol well contains only 180 μL of HBSS without tested compound. Theplate was placed at room temperature for 30 min.

2.6 To each well was added 20 μL of 50 μM ¹⁴C-Uric acid. The plate wasplaced at room temperature for 20 min.

2.7 The solution in each well was removed and the cells in each wellwere washed with pre-cooled HBSS buffer. To each well was added 0.2 MNaOH to dissolve the cells. The solution containing cell fragments wascollected and the right amount of scintillation liquid was added. Theradioisotope intensity of the ¹⁴C-Uric acid (CPM value) was thendetected by using PerkinElmer MicroBeta Trilux 1450 liquid scintillationanalyzer.

2.8 All tests were repeated three times, and the results were averagedand the standard deviation (SD) was calculated. The formula forcalculating the inhibitory rate of uric acid transport for compounds wasshown as below:

${{InhibitoryRate}\mspace{14mu} (\%)} = {\frac{{{CPM}\mspace{14mu} {of}\mspace{14mu} {Blank}\mspace{14mu} {control}\mspace{14mu} {well}} - {{CPM}\mspace{14mu} {of}\mspace{14mu} {Test}\mspace{14mu} {compound}\mspace{14mu} {well}}}{{CPM}\mspace{14mu} {of}\mspace{14mu} {Blank}\mspace{14mu} {control}\mspace{14mu} {well}} \times 100\%}$

3. Test Results

The inhibitory rates of uric acid transport for compounds 4, 5, 9, 11,12, 18, 19, 29, 30, 33, 38, 39, 41, 45, 51, 52, 56, 69, 74, 75, andbenzbromarone at 500 nM were obtained according to the aboveexperimental procedures. The tested results were listed in table 1. Theresults showed that in comparison with the control drug benzbromarone,the compounds have equal or better inhibitory effect of uric acidtransport in HEK293-hURAT1 transfection cell line.

TABLE 1 Inhibitory rates of uric acid transport for test compounds andbenzbromarone at 500 nM in HEK293-hURAT1 transfection cell line Compoundnumber Inhibitory rates of uric acid or drug transport, ±SD (%) BBR55.57 ± 1.42  4 71.68 ± 1.84  5 63.00 ± 3.33  9 60.63 ± 0.82 11 63.55 ±0.95 12 56.24 ± 0.12 18 65.44 ± 0.71 19 68.84 ± 2.83 29 64.35 ± 0.12 3068.05 ± 1.49 33 65.06 ± 0.39 38 62.41 ± 0.72 39 64.12 ± 2.25 41 55.53 ±1.02 45 62.93 ± 3.34 51 61.32 ± 1.10 52 57.50 ± 3.61 56 62.80 ± 9.34 6971.10 ± 2.50 74 62.75 ± 5.73 75 62.58 ± 0.84 BBR: benzbromarone.

Example 33: Cytotoxicity Test of Compounds on the Human Normal LiverCell Lines L-02 and WRL-68

It has been reported that benzbromarone has a serious hepatotoxicity.Therefore, benzbromarone was used as a positive control drug in thisassay. The cytotoxicity of the compounds on two human normal liver celllines L-02 and WRL-68 was tested, respectively.

1. Materials

The human normal liver cell line L-02 was purchased from Procell LifeScience & Technology Co., Ltd. The human normal liver cell line WRL-68was given by the Life Science Institute of Nanjing University.Benzbromarone, Resazurin, and Methylene blue were purchased fromSigma-Aldrich Co. LLC. Potassium ferricyanide and potassium ferrocyanidewere purchased from Aladdin (Shanghai) Biological Technology Co., Ltd.DMEM culture medium, phenol red free DMEM culture medium, and fetalbovine serum were purchased from Thermo Fisher Scientific Inc.Penicillin and streptomycin were purchased from Beyotime BiotechnologyCo., Ltd.

2. Experimental Methods

2.1 The normal liver cell lines L-02 and WRL-68 were cultured with DMEMculture medium (containing 10% of fetal bovine serum, 100 U/mL ofpenicillin and 0.1 mg/mL of streptomycin) in an incubator under 5% CO₂at 37° C. until the cell density was about 90%, respectively.

2.2 The cells were inoculated to a 96-well plate at a cell population of1×10³/well and then cultured in an incubator under 5% CO₂ at 37° C. for24 h.

2.3 Tested compounds and benzbromarone at different concentrationgradients were prepared by using the DMEM culture medium and added intowells at 100 μL/well as compounds wells. The DMEM culture medium wasadded into wells at 100 μL/well without tested compound as negativecontrol wells. All plates were placed in an incubator under 5% CO₂ at37° C. for 120 h.

2.4 Resazurin (15 mg/50 mL, 200×), Methylene Blue (25 mg/10 mL, 1000×),Potassium ferricyanide (0.329 g/100 mL, 100×) and Potassium ferrocyanide(0.422 g/100 mL, 100×) were dissolved into PBS (0.1 M, pH=7.4) to obtain10×Alamar Blue solution for standby. This 10×Alamar Blue solution wasdiluted into 1×Alamar Blue solution with phenol red free DMEM culturemedium before use.

2.5 The cells were washed with PBS (0.1 M, pH=7.4) twice. The AlamarBlue solution was added into wells at 100 μL/well. 100 μL of Alamar Bluesolution was added into wells without cells to serve as blank controlwells. The 96-well plate was placed in an incubator under 5% CO₂ at 37°C. for 3 h. Each concentration of compound was repeated three timesduring the test.

2.6 The fluorescence value of the cells was detected at Ex 530/Em 590 nmby ELISA Victor X4 (Perkin Elmer). The fluorescence value of the cellscontaining compound is the F_((test compound)); the fluorescence valueof the cells without compound as blank control is theF_((blank control)); the fluorescent value of the cells from negativecontrol group is F_((negative control)). The average value and standarddeviation of cell viability of three repeated concentrations wascalculated by the following formula:

${{Cell}\mspace{14mu} {viability}\mspace{14mu} (\%)} = {\frac{F_{({{test}\mspace{14mu} {compound}})} - F_{({{blank}\mspace{14mu} {control}})}}{F_{({{negative}\mspace{14mu} {control}})} - F_{({{blank}\mspace{14mu} {control}})}} \times 100\%}$

2.7 The half inhibitory concentration (IC₅₀) of the compound for thecells L-02 and WRL-68 was obtained from the cell viability by PrismGraph software.

3. Test Results

The half inhibitory concentration (IC₅₀) of compounds 4, 5, 9, 18, 33,38, 39, 45, 51, 52, 56, 69, 74, and 75 against the human normal livercell lines L-02 and WRL-68 are greater than 100 μM. The IC₅₀ ofBenzbromarone for L-02 and WRL-68 was 40.17 μM and 45.54 μM,respectively.

Example 34: Uric Acid Excretion Test of Compound 74 in HyperuricemiaMice

1. Materials

1.1 Preparation of Tested Compound 74 and Benzbromarone

To compound 74 or benzbromarone was added certain amount of 0.5% CMC-Nasolution and the mixture was stirred at room temperature to obtain asuspension based on the designed dosage, respectively.

1.2 Animals

Species: Kingming mice (Clean Level); body weights: 25 to 30 g; ages: 4to 5 weeks; sex: male. These mice were purchased from Shanghai SLACLaboratory Animal Co., Ltd. Certificate No.: SCXK (HU) 2012-2002. Animalquality certificate number: 2015000522173.

1.3 Reagents

Yeast extract powder was purchased from Beijing Aoxing Biology Co., Ltd.Adenine and potassium oxonate were purchased from Aladdin (Shanghai)Biological Technology Co., Ltd. CMC-Na was purchased from SinopharmChemical Reagent Co., Ltd. Uric acid assay kit (phosphotungstic acidmethod) was purchased from Nanjing Jiancheng Bioengineering Institute.

2. Experimental Methods

2.1 Preparation of a Mixed Suspension of Yeast Extract and Adenine

A certain amount of adenine and yeast extract powder was weighted and acertain amount of double distilled water was added. The mixture wasstirred at about 60° C. for 40 min to give a suspension, which theconcentration of yeast extract is 0.6 g/mL and the concentration ofadenine is 12 mg/mL.

2.2 Preparation of Potassium Oxonate Suspension

A suspension of 20 mg/mL potassium oxonate was prepared by mixing acertain amount of potassium oxonate with 0.5% CMC-Na solution beforeuse.

2.3 the Establishment of Hyperuricemia Mice Model and Administration ofTested Materials

Male Kunming mice were randomly divided into four groups: blank controlgroup, model group, compound 74 group, and benzbromarone group. Eachgroup has six mice. All mice fasted 2 to 3 h before use. The modelgroup, benzbromarone group, and compound 74 group were orally given asuspension of yeast extract and adenine prepared above to reach thefinal dosage of 10 g/kg (body weight) of yeast extract and 200 mg/kg(body weight) of adenine, respectively. The blank control group was onlygiven same volume of normal saline orally. After 2.5 h, all mice incompound 74 group and benzbromarone group were given 10 mL/kg ofsuspension of compound 74 (1.5 mg/mL) and 10 mL/kg of suspension ofbenzbromarone (1.5 mg/mL), respectively. The blank control group andmodel group were orally given same volume of 0.5% CMC-Na solution. Allanimals were treated in the same way for seven days by usingadministration methods described above. On the last day, afteradministration of a suspension of yeast extract and adenine for themodel group, compound 74 group, and benzbromarone group, all mice inthese three groups were given 12.5 mL/kg of potassium oxonate (20 mg/mL)by i.p. The blank control was only given same volume of 0.5% CMC-Nasolution by i.p. After 30 min, compound 74 and benzbromarone wereadministrated orally to the mice at same dosages as above in compound 74group and benzbromarone group, respectively. The blank control group andmodel group were orally given same volume of 0.5% CMC-Na solution.

2.3 Sample Collection and Analysis

Collection of urine samples: All mice were placed in metabolic cageswith normal diet individually after giving test compounds on the lastday. 24 h urine was collected and the urine volume was measured. Theurine was centrifugated at 3000 rpm for 20 min and the supernatant wascollected.

Detection of the concentration of uric acid of mice urine samples: uricacid concentration in samples was detected by using uric acid assay kit(phosphotungstic acid method) followed the procedures described in theinstruction.

3. Test Results

The results of promoting uric acid excretion in hyperuricemia mice werelisted in table 2. Both compound 74 and benzbromarone significantlyincreased uric acid excretion in hyperuricemia mice. The efficacy ofcompound 74 in promotion of uric acid excretion was significantly betterthan benzbromarone. Compared with the model group of hyperuricemia mice,the uric acid excretion of compound 74 was increased by about 46.77%,while the excretion of uric acid excretion of benzbromarone wasincreased by about 25.35%.

TABLE 2 Uric acid excretion test of compound 74 and benzbromarone byoral administration in hyperuricemia mice Changes of uric Uric acid inacid excretion Mice Dose urine for 24 h, (compared with Group numbers(mg/kg) ±SD (mmol) model group, %) Blank 6 /  6.80 ± 2.17 63.61 controlModel 6 / 10.69 ± 1.48^(##) 100 BBR 6 15 13.40 ± 1.59* 125.35 Compound 615 15.69 ± 1.53**^(▴) 146.77 74 The excretion change of uric acid amountin the model group is set to 100%. vs. blank control group, ^(##)means:P < 0.01. vs. model group, *means: P < 0.05, **means: P < 0.01. vs.Benzbromarone group, ^(▴)means: P < 0.05.

Example 35: Study on Acute Toxicity of Single Dose of Compound 74 inRats

1. Materials

1.1 Preparation of Tested Compound 74 and Benzbromarone

Compound 74 and benzbromarone were ground, and certain amount of 0.5%CMC-Na solution was added to prepare a suspension, respectively, beforeuse. Benzbromarone was purchased from Mianyang Kaixing PharmaceuticalTechnology Co., Ltd. Lot Number is BXML-201506005.

1.2 Animals

Species: SD rats (SPF Level); body weights: 120 to 180 g; ages: 5 to 6weeks. Source: purchased from Animal Research Center of WuhanUniversity; certificate No.: SCXK (E) 2014-0004; animal qualitycertificate number: 2015000522173.

2. Experimental Methods and Results

In the pre-experiment of acute toxicity in rats, the highest dose at 5g/kg of compound 74 did not cause death of rats. Therefore, the dosageof compound 74 was determined to be 5 g/kg in this assay. When the doseof benzbromarone was 0.14 g/kg in the pre-experiment, no death of ratswas found. Therefore, the dosage of benzbromarone was determined to be0.14 g/kg in this assay.

Rats were randomly divided into group A1, group B1 and blank controlgroup. Each group has 10 of rats with half male and half female. Asingle dose of compound 74 suspension, benzbromarone suspension, and0.5% CMC-Na solution at 20 mL/kg was given by oral administration togroup A1, group B1, and blank control group, respectively, after 6 h offasting.

The dosage and death rate of every group were shown in table 3. Noimmediate toxicity was found in each group and delayed toxicity was notfound in the observation period from 24 h to 14 days. All rats survivedand were in good condition with weight gain. The weight changes werelisted in table 4. The maximum tolerated dose of compound 74 andbenzbromarone in acute toxicity test were 5 g/kg and 0.14 g/kg,respectively.

TABLE 3 The dosage and death rate of SD rats in each group Sample Dosagequantity Volume Concentration Death Group Sample (g/kg) (mg) (mL)(mg/mL) rate A1 74 5.0 7520.9 30.0 250 0/10 B1 BBR 0.14 272.2 38.9 70/10 Each group has 10 rats.

TABLE 4 Weight changes of SD rats in each group No. and Weight sex gainSam- of 0 day 7 day 14 day rate ple rats (X ± SD) (g) (X ± SD) (g) (X ±SD) (g) (%) 74 5 (M) 149.06 ± 5.95 204.04 ± 21.69 258.12 ± 17.65 +73.2 5(F) 135.94 ± 5.62 183.02 ± 11.10 208.04 ± 11.90 +53.0 BBR 5 (M 149.36 ±3.25 207.80 ± 8.72  273.88 ± 13.54 +83.4 5 (F) 139.04 ± 6.60 175.00 ±6.24  201.30 ± 19.84 +44.8 blank 5 (M) 147.64 ± 4.48 191.16 ± 13.65248.34 ± 23.13 +68.2 con- 5 (F) 134.20 ± 4.07 173.28 ± 9.27  204.44 ±15.70 +52.3 trol “Weight gain rate” means the weight of rats in 14 daycompared with 0 day, and “+” means the weight was increased.

Example 36: Study on Pharmacokinetics of Compound 74 FollowingIntravenous and Oral Administration in SD Rats

1. Materials

1.1 Preparation of Solution of Tested Compound 74

Dose formulation preparation for PO: Weight out the required amount ofcompound 74. Added approximately 70% of 0.5% CMC-Na with stirring,vortexing and sonication to mix well until visually well suspension.Then added the remaining vehicle to target total volume and vortex-mix.

Dose formulation preparation for IV: Weight out the required amount ofcompound 74. Added appropriate DMSO with sonication until dissolved,then added appropriate HP-B-Cyclodextrin water solution (20%, w/v) withvortexing to mix well.

1.2 Animals

Species: SD rats (SPF Level); sex: male; source: Sino-British SIPPR/BKLab Animal Ltd., Shanghai.

2. Methods

2.1 Dose and Administration

The animals that dosed via orally were fasted overnight (10-14 hours)prior to oral administration. Food supply to the animals dosed orallywere resumed 4 h post-dose. Dose administration information is presentedin table 5.

TABLE 5 The dosage of compound to SD rats Concen- Vol- Weight Dosagetration ume Route of Sample Group (g) (mg/kg) (mg/mL) (mL)Administration 74 A-1 188.2 10 1 1.9 Oral (PO) 197.3 2.0 213.0 2.1 A-2207.8 1 0.2 1.0 Intravenous 221.1 1.1 (IV) 220.9 1.1

2.2 Sample Collection and Bioanalysis

Blood samples (approximately 250 μL/sample) were collected via jugularvein at Pre-dose and Post-dose (5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6h, 8 h, and 24 h). Blood samples were placed into tubes containingsodium heparin and centrifuged conditions at 8000 rpm for 6 minutes at2-8° C. to separate plasma from the samples. Plasma sample (50 μL) weretransferred to tube, then 250 μL IS solution (200 ng/mL Tolbutamide) wasadded to it. After vortexing for 1 min and centrifuging for 5 min at15000 rpm, 200 μL aliquots of supernatant were transferred to 96-wellplate for LC-MS/MS analysis. The calibration curve of compound 74 wasranging from 1 to 1000 ng/mL. The LLOQ is 1 ng/mL for plasma.

2.3 Pharmacokinetic Analysis

A non-compartemental module of WinNonlin® Professional 5.2 was used tocalculate parameters. The bioavailability was calculated as F%=(Dose_((IV))×AUC_((0-t)(PO)))/(Dose_((PO))×AUC_((0-t)(IV)))×100%.

3. Results

The pharmacokinetic parameters of the SD rats with compound 74 obtainedfrom the above methods are shown in table 6. Compound 74 of thisinvention has good pharmacokinetic parameters and high bioavailabilityin SD rats.

TABLE 6 Pharmacokinetics Parameters of compound 74 in SD rats followingoral administration and intravenous administration oral administration(PO: 10 mg/kg) Rats t_(1/2) T_(max) C_(max) AUC_((0-t)) MRT_((0-∞)) F*No. (h) (h) (ng/mL) (ng/mL*h) (h) (%) 101 2.70 2.00 8251.74 89284.206.00 100.28 102 2.90 2.00 9205.06 89890.12 5.90 100.96 103 3.00 6.006976.14 96188.83 6.80 108.04 Mean 2.90 3.30 8144.31 91787.72 6.30 103.09SD 0.10 2.30 1118.34 3823.50 0.50 4.29 intravenous administration (IV: 1mg/kg) Rats t_(1/2) T_(max) C_(max) AUC_((0-t)) Vz Clz MRT_((0-∞)) No.(h) (h) (ng/mL) (ng/mL*h) (mL/kg) (mL/h/kg) (h) 201 5.40 0.10 5494.598786.13 858.55 110.23 5.40 202 6.00 0.10 6705.53 9076.84 917.79 105.665.60 203 6.00 0.10 6885.21 8847.27 934.49 108.65 5.40 Mean 5.80 0.106361.78 8903.41 903.61 108.18 5.50 SD 0.30 0.00 756.36 153.27 39.90 2.320.10 *Obtained from AUC_((0-t))

1. A compound having a general chemical Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently selected from the group consisting of hydrogen, deuterium,halogen, cyano, hydroxyl, C₁₋₅ alkyl, substituted C₁₋₅ alkyl, C₁₋₃alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃ alkylthio, or substituted C₁₋₃alkylthio in one or more; R³ is selected from the substituted orunsubstituted group consisting of C₁₋₄ alkyl or C₃₋₄ cycloalkyl, and itssubstituents are selected from the group consisting of deuterium,halogen, C₁₋₂ alkyl or C₃₋₄ cycloalkyl; R⁴ and R⁵ are independentlyselected from the group consisting of hydrogen, deuterium, halogen,cyano, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkyl, substituted C₁₋₃ alkyl,C₁₋₃ alkoxy, substituted C₁₋₃ alkoxy, C₁₋₃ alkylthio, or substitutedC₁₋₃ alkylthio; wherein the substituents in R¹, R², R⁴, and R⁵ areindependently selected from deuterium, halogen, C₁₋₃ alkyl, C₃₋₄cycloalkyl or C₁₋₃ alkoxy.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently selected from the group consisting of hydrogen, deuterium,fluorine, chlorine, bromine, cyano, hydroxyl, C₁₋₃ alkyl, substitutedC₁₋₃ alkyl, C₁₋₃ alkoxy, or substituted C₁₋₃ alkoxy; Wherein thesubstituents are independently selected from the group consisting ofdeuterium, halogen, C₁₋₃ alkyl, C₃₋₄ cycloalkyl or C₁₋₃ alkoxy.
 3. Thecompound of claim 2 or a pharmaceutically acceptable salt thereof,wherein: R¹ and R² are independently selected from the group consistingof hydrogen, deuterium, fluorine, chlorine, bromine, CN, C₁₋₃ alkyl,C₁₋₃ halogenated alkyl or C₁₋₃ alkoxy.
 4. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein: R³ is selected fromthe substituted or unsubstituted group consisting of C₁₋₃ alkyl and C₃₋₄cycloalkyl; Wherein the substituents are independently selected from thegroup consisting of deuterium, halogen, C₁₋₂ alkyl or C₃₋₄ cycloalkyl.5. The compound of claim 1, wherein: R⁴ and R⁵ are independentlyselected from the group consisting of hydrogen, deuterium, halogen,cyano, ethylene, acetylene, C₁₋₂ alkyl, substituted C₁₋₂ alkyl, C₁₋₂alkoxy, substituted C₁₋₂ alkoxy, C₁₋₂ alkylthio, or substituted C₁₋₂alkylthio; Wherein the substituents are independently selected from thegroup consisting of deuterium, halogen, C₁₋₂ alkyl, C₃₋₄ cycloalkyl orC₁₋₃ alkoxy.
 6. The compound of claim 1, wherein: R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, deuterium,halogen, cyano, C₁₋₂ alkyl, C₁₋₂ halogenated alkyl, C₁₋₂ alkoxy or C₁₋₂alkylthio.
 7. The compound of claim 1, wherein the compound is selectedfrom the group consisting of:(3,5-Dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;(2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone;(3-Chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;3-Chloro-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile;(3-Bromo-4-hydroxy-5-iodophenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;(2-Ethylimidazo[1,2-a]pyridine-3-yl)(4-hydroxy-3-iodo-5-methylphenyl)methanone;(3-Bromo-5-chloro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone;(3-Chloro-4-hydroxy-5-iodophenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-yl)methanone;5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-methylbenzonitrile;(3-Bromo-4-hydroxy-5-(trifluoromethyl)phenyl)(2-ethylimidazo[1,2-a]-pyridine-3-yl)methanone;(3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-methylimidazo[1,2-a]pyridine-3-yl)methanone;(3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-methoxyimidazo[1,2-a]pyridine-3-yl)methanone;(2-Ethylimidazo[1,2-a]pyridin-3-yl)(2-(ethylthio)-4-hydroxyphenyl)methanone;3-Bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile;5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile;5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-3-fluoro-2-hydroxybenzonitrile;(3,5-Dibromo-4-hydroxyphenyl)(2-propylimidazo[1,2-a]pyridine-3-yl)methanone;(3-Bromo-5-chloro-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone;(3-Bromo-5-fluoro-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanone;(2-Ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)(3-fluoro-4-hydroxy-5-iodophenyl)methanone;(3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxyimidazo[1,2-a]pyridin-3-yl)methanone;(6-Bromo-2-ethyl-7-methylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)-methanone;(3,5-Dibromo-4-hydroxyphenyl)(2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-methanone;3-(3,5-Dibromo-4-hydroxyphenyl)-2-ethylimidazo[1,2-a]pyridine-6-carbonitrile;(2-Deuterium-3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyridine-3-yl)methanone;(6-Deuterium-2-ethylimidazo[1,2-a]pyridine-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone;(2-Cyclopropylimidazo[1,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone;3-Bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrilehydrogen chloride; and5-(2-Ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrilehydrogen chloride.
 8. A pharmaceutical acceptable composition comprisingthe compound of claim 1 or its pharmaceutically acceptable salt asactive ingredient or main active ingredient, and a pharmaceuticallyacceptable carrier.
 9. A method for treating and preventing a metabolicdisease in uric acid excretion comprising a step of administrating to asubject in need a therapeutically effective amount of the compound ofclaim 1 or its pharmaceutically acceptable salt.
 10. The method of claim9, the metabolic disease is hyperuricemia, nephrosis or gout.